1. Field of the Invention
The present invention relates generally to the field of medicinal chemistry and medicine. More particularly, it concerns compositions and methods for treating neurological or mitochondrial diseases or injury.
2. Description of Related Art
An increasing amount of experimental evidence implicates oxidative stress as one of the major causes of delayed cell death in a variety of neurodegenerative diseases, as well as in stroke, trauma, and seizures. In many of these diseases and disorders, mitochondrial generated reactive oxygen species react with and damage cellular components, resulting in caspase independent cell death (Beckman and Ames, 1998; Simonian and Coyle, 1996; Halliwell, 2001). In addition, one of the hallmarks of oxidative stress is a decrease in the reduced form of the major cellular antioxidant, glutathione (GSH), which has been suggested to play a key role in the degeneration of dopaminergic neurons (Riederer et al., 1989; Sofic et al., 1992). Neuronal GSH synthesis is largely dependent on the exchange of intracellular glutamate for extracellular cystine via the cystine/glutamate antiporter. Concentrations of extracellular glutamate as low as 100 μM inhibit this antiporter (Sagara and Schubert, 1998), and it has been previously reported that extracellular levels of glutamate in the central nervous system (CNS) can reach concentrations as high as 10 mM following injury (Matsumoto et al., 1996). This depletion of GSH leads to a unique form of mitochondrial driven programmed necrotic cell death (necroapoptosis or oxytosis), which does not depend on caspase activation (Albrecht et al., 2010.). Recent studies have shown programmed necrotic cell death to be a tightly controlled process involving multiple inter-connected kinases, RIP1, RIP3, MLKL, and the mitochondrial phosphatase, phosphoglycerate mutase family member 5 (PGAM5), via its regulation of dynamin-related protein 1 (Drp-1) and subsequent mitochondrial fragmentation. In addition, PGAM5 has been shown to be at the convergent point of multiple cell death pathways. Knock-down of PGAM5 prevents both extrinsic (Tumor-necrosis factor-α) and intrinsic (tert-butyl hydroperoxide, and calcium ionophore) induced cell death (Wang et al., 2012).
Vitamin K (VK) is a group of structurally similar, fat soluble vitamins that play well known roles in the post-translational modification of proteins required for blood coagulation and bone metabolism (Suttie, 1980; Price, 1988). There are two forms of naturally occurring VK, phylloquinone (VK1) and the menaquinones (VK2). A synthetic form of VK, menadione (VK3) is also available and used in animal feeds and supplements. All forms of VK possess a common 2-methyl-1,4-naphthoquinone core structure, but individual forms differ in the length and degree of saturation of an aliphatic side chain attached to the 3′ position. VK1, found primarily in green leafy vegetables (Shearer et al., 1996), is a single compound containing a saturated side chain consisting of four isoprenoid subunits. While it is the major dietary source of VK, post mortem (Thijssen and Drittij-Reijinders, 1996) and animal studies have indicated that concentrations are significantly lower in the brain and other tissues compared with the VK2. There are several forms of VK2 that are classified based on the length of the unsaturated 3′ side chain. The major form of VK2 (>90%) found in animal tissues has a four isoprenoid unit (geranylgeranyl) side chain. Although there is a small dietary presence of VK2, it is primarily obtained by removal of the phytyl group of VK1 followed by a subsequent geranylgeranylation that has been shown to occur in cultured primary brain slices and neurons, indicating an as of yet unknown but important function for VK2 in brain function (Nagai, 1979).
VK2 does not effectively cross the blood-brain barrier. Thus, there is a need for synthetic compositions that can cross the blood-brain barrier that may be used to treat conditions associated with a VK deficiency. Clearly there is a need for new compounds and methods for treating neurological diseases and injury.